1. Field of the Invention
The present invention relates to novel 1,3-dihydro-2H-indol-2-one derivatives, to a process for preparing them and to pharmaceutical compositions containing them.
2. Description of the Art
The compounds according to the present invention have affinity for and selectivity towards the V1b receptors or towards both the V1b and V1a receptors of arginine-vasopressin (AVP).
AVP is a hormone which is known for its antidiuretic effect and its effect in regulating arterial pressure. It stimulates several types of receptor: V1 (V1a, V1b), V2. These receptors are located in particular in the liver, the vessels (coronary, renal and cerebral), the platelets, the kidneys, the uterus, the adrenal glands, the pancreas, the central nervous system and the pituitary gland. AVP thus exerts cardiovascular, hepatic, pancreatic, antidiuretic and platelet-aggregating effects and effects on the central and peripheral nervous system, and on the uterine sphere.
The location of the various receptors is described in: S. Jard et al., Vasopressin and oxytocin receptors: an overview, in Progress in Endocrinology. H. Imura and K. Shizurne ed., Experta Medica, Amsterdam, 1988, 1183-1188, as well as in the following articles: J. Lab. Clin. Med., 1989, 114, (6), 617-632 and Pharmacol. Rev., 1991, 43 (1), 73-108.
More particularly, the AVP V1a receptors are located in many peripheral organs and in the brain. They have been cloned in rats and man and they regulate most of the known effects of AVP: platelet aggregation; uterine contractions; the contraction of blood vessels; secretion of aldosterone, cortisol, CRF (corticotropin-releasing factor) and adrenocorticotrophic hormone (ACTH); hepatic glycogenolysis, cell proliferation and the main central effects of AVP (hypothermia, memory, etc.).
The V1b receptors were initially identified in the adenohypophysis of various animal species (rats, pigs, bovines, sheep, etc.) including man (S. Jard et al., Mol. Pharmacol., 1986, 30, 171-177; Y. Arsenijevic et al., J. Endocrinol., 1994, 141, 383-391; J. Schwartz et al., Endocrinology, 1991, 129(2), 1107-1109; Y. De Keyser et al., FEBS Letters, 1994, 356, 215-220) in which they stimulate the release of adrenocorticotrophic hormone via AVP and potentiate the effects of CRF on the release of ACTH (G. E. Gillies et al., Nature, 1982, 299, 355). In the hypothalamus, the V1b receptors also induce a direct release of CRF (Neuroendocrinology, 1994, 60, 503-508) and are, in these various respects, involved in stress situations.
These V1b receptors have been cloned in rats, man and mice (Y. De Keyser, FEBS Letters, 1994, 356, 215-220; T. Sugimoto et al., J. Biol. Chem. 1994, 269(43), 27088-27092; M. Saito et al., Biochem. Biophys. Res. Commun., 1995, 212 (3), 751-757; S. J. Lolait et al., Neurobiology, 1996, 92, 6783-6787; M. A. Ventura et al., Journal of Molecular Endocrinology, 1999, 22, 251-260) and various studies (in situ hybridization, PCR [polymerase chain reaction], etc.) reveal the ubiquitous presence of these receptors in various central tissues (brain, hypothalamus and adenohypophysis in particular) and peripheral tissues (kidney, pancreas, adrenals, heart, lungs, intestine, stomach, liver, mesentery, bladder, thymus, spleen, uterus, retina, thyroid, etc.) and in certain tumors (hypophyseal, pulmonary, etc.) suggesting a broad biological and/or pathological role for these receptors and a potential involvement in various diseases.
By way of example, in rats, studies have shown that AVP regulates the endocrine pancreas, via the V1b receptors, by stimulating the secretion of insulin and glucagon (B. Lee et al., Am. J. Physiol. 269 (Endocrinol. Metab. 32): E1095-E1100, 1995) or the production of catecholamines in the medullo-adrenal which is the site of a local synthesis of AVP (E. Grazzini et al., Endocrinology, 1996, 137(a), 3906-3914). Thus, in the latter tissue, AVP is thought to have a crucial role, via these receptors, in certain types of adrenal pheochromocytomas which secrete AVP and thereby induce a sustained production of catecholamines which are the cause of hypertension and which are resistant to angiotensin II-receptor antagonists and to conversion enzyme inhibitors. The adrenal cortex is also rich in V1a receptors involved in the production of glucocorticoids and mineralocorticoids (aldosterone and cortisol). Via these receptors, AVP (in the circulation or synthesized locally) can induce a production of aldosterone with an efficacy which is comparable to that of angiotensin II (G. Guillon et al., Endocrinology, 1995, 136(3), 1285-1295). Cortisol is a powerful regulator of the production of ACTH, the stress hormone.
Recent studies have also shown that the adrenal glands are capable of directly releasing CRF and/or ACTH via activation of the V1b and/or V1a receptors borne by the medullary cells (G. Mazzocchi et al., Peptides, 1997, 18(2), 191-195; E. Grazzini et al., J. Clin. Endocrinol. Metab., 1999, 84(6), 2195-2203).
The V1b receptors are also considered as a label for ACTH-secreting tumors such as certain pituitary tumors, certain bronchial carcinomas (SCLC [small lung cell cancers]), pancreatic, adrenal and thyroid carcinomas, inducing Cushing's, syndrome in certain cases (J. Bertherat et al., Eur. J. Endocrinol., 1996, 135, 173; G. A. Wittert et al., Lancet, 1990, 335, 991-994; G. Dickstein et al., J. Clin. Endocrinol. Metab., 1996, 81(8), 2934-2941). As regards the V1a receptors, they are a more specific label for small cell lung cancers (SCLC) (P. J. Woll et al., Biochem. Biophys. Res. Commun., 1989, 164(1), 66-73). Thus, the compounds according to the present invention are obvious diagnostic tools and offer a novel therapeutic approach in the proliferation and detection of these tumors, even at an early stage (radiolabelling; SPECT [single photon emission computed tomography]; PET scan [positron emission tomography scanner]).
The abundant presence of the V1b receptor messenger in the stomach and intestine suggests an involvement of AVP via this receptor on the release of gastrointestinal hormones such as cholecystokinin, gastrin or secretin (T. Sugimoto et al., Molecular cloning and functional expression of V1b receptor gene, in Neurohypophysis: Recent Progress of Vasopressin and Oxytocin Research; T. Saito, K. Kurokawa and S. Yoshida ed., Elvesier Science, 1995, 409-413).
1,3-Dihydro-2H-indol-2-one derivatives have been described in certain patent applications as arginine-vasopressin receptor ligands and/or oxytocin receptor ligands: mention may be made of patent applications WO 93/15051, EP-A-0 636 608. EP-A-0 636 609, WO 95/18105, WO 97/15556 and WO 98/25901.
No non-peptide compound with affinity for and selectivity towards the V1b receptors or simultaneously for and towards both the V1b and V1a receptors of arginine-vasopressin is known to date.
Novel 1,3-dihydro-2H-indol-2-one derivatives have now been found which have affinity for and selectivity towards the V1b receptors or for and towards both the V1b and V1a receptors of arginine-vasopressin.
These compounds may be used for the preparation of medicinal products that are useful in the treatment or prevention of any pathology in which arginine-vasopressin and/or the V1b receptors or both the V1b receptors and the V1a receptors are involved, in particular in the treatment or prevention of complaints of the cardiovascular system, for example hypertension; of the central nervous system, for example stress, anxiety, depression, compulsive obsessive disorder and panic attacks; of the renal system; of the gastric system as well as in the treatment of small cell lung cancers; of obesity; of type II diabetes; of insulin resistance; of hypertriglyceridemia; of atherosclerosis; of Cushing's syndrome; of any pathology following stress and chronic stress states.
All of the references described hereinabove are incorporated herein by reference in their entirety.